Distinct Effects of Tissue-Type Plasminogen Activator and SMTP-7 on Cerebrovascular Inflammation Following Thrombolytic Reperfusion
Distinct Effects of Tissue-Type Plasminogen Activator and SMTP-7 on Cerebrovascular Inflammation Following Thrombolytic Reperfusion
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DOI：
10.1161/strokeaha.110.598359
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发表时间：
2011-04-01
期刊：
影响因子：
8.3
通讯作者：
Honda, Kazuo
中科院分区：
文献类型：
--
作者：
Miyazaki, Takuro;Kimura, Yuji;Honda, Kazuo
背景和目的：使用组织型纤溶酶原激活剂（t-PA）进行溶栓治疗偶尔会伴有有害的结果，包括脑出血。我们报道了候选溶栓药物Stachybotrys microspora triprenyl phenol-7 （SMTP-7）对小鼠栓塞性脑卒中模型脑梗死有良好的治疗效果；然而，关于这种药物是否影响溶栓再灌注后的脑血管炎症，我们知之甚少。本研究旨在比较重组t-PA （rt-PA）和SMTP-7对脑血管炎症的影响。方法采用光化学诱导的小鼠血栓性大脑中动脉闭塞（tMCAo）模型，研究rt-PA-和smtp -7诱导的溶栓再灌注对白细胞动力学的影响。结果：rt-PA和SMTP-7给药（各10 mg/kg）均可导致小鼠溶栓性再灌注。smtp -7给药小鼠在大脑中静脉血管壁上出现相对轻微的白细胞滚动和附着，有较弱的过氧亚硝酸盐反应和促炎基因（IL-1 β、tnf - α、ICAM-1和VCAM-1）的表达；因此，与给予rt- pa的小鼠相比，梗死体积较小。体外研究表明，20 μ g/mL的rt-PA能促进细胞因子诱导的内皮细胞活性氧的产生，而类似浓度的SMTP-7则不能；此外，SMTP-7抑制细胞因子诱导的VCAM-1诱导和白细胞/内皮细胞粘附。结论：与rt-PA小鼠相比，SMTP-7小鼠相对轻微的脑血管炎症和脑梗死被认为至少部分是由SMTP-7在ECs中的直接抗氧化作用引起的。(中风。2011;42:1097 - 1104)。
Background and Purpose-Thrombolysis therapy using tissue-type plasminogen activator (t-PA) is occasionally accompanied by harmful outcomes, including intracerebral hemorrhage. We have reported that Stachybotrys microspora triprenyl phenol-7 (SMTP-7), a candidate thrombolytic drug, has excellent therapeutic effect on cerebral infarction in embolic stroke model in mice; however, little is known regarding whether this agent influences cerebrovascular inflammation following thrombolytic reperfusion. The current study aimed to compare the effects of recombinant t-PA (rt-PA) and SMTP-7 on cerebrovascular inflammation.Methods-The impact of rt-PA- and SMTP-7-induced thrombolytic reperfusion on leukocyte dynamics was investigated in a photochemically induced thrombotic middle cerebral artery occlusion (tMCAo) model in mice.Results-Both rt-PA and SMTP-7 administration in tMCAo mice (each 10 mg/kg) resulted in thrombolytic reperfusion. The SMTP-7-administered mice showed relatively mild rolling and attachment of leukocytes to the vascular wall in the middle cerebral vein, with weak peroxynitrite reactions and proinflammatory gene expression (IL-1 beta, TNF-alpha, ICAM-1, and VCAM-1); thus, a small infarct volume compared with rt-PA-administered mice. In vitro study suggested that rt-PA at 20 mu g/mL, but not SMTP-7 at a similar concentration, promotes cytokine-induced reactive oxygen species generation in cultured endothelial cells; moreover, SMTP-7 suppressed cytokine-induced VCAM-1 induction in the cells and leukocyte/endothelial cell adhesions.Conclusions-Relatively mild cerebrovascular inflammation and cerebral infarction in the SMTP-7 mice, compared with in rt-PA mice, is thought to be caused at least in part by direct antioxidative actions of SMTP-7 in ECs. (Stroke. 2011;42:1097-1104.)